In vitro diagnostic (IVD) devices are a complex group of products that have been regulated in Europe in the same way since the 1998 IVD Directive. Importantly, since the 1990s, the level of complexity of IVD devices has dramatically changed and continued to evolve, with the emergence of companion diagnostics and higher complexity tests. The new EU IVD Regulation has long been on the cusp of publication, and as this gets closer it is clear that all will change.
Looking back at 98/79/EC or the IVD Device Directive, the European framework for these products is essentially a positive inclusion list. There are two lists within the IVD Directive, namely List A and List B. If a product is not included in either list, is not a self-test or is non-sterile, the product is ‘classified’ as a general IVD.
List A of the IVD Directive contains a set of product types that were perceived to have the highest level of risk (e.g. reagents for detection of HIV infection). List B contains a set of product types that were perceived to have a lower level of risk, for example reagents for determining infection to specific human infections (e.g. cytomegalovirus).
With the IVD Directive lists being so prescriptive, it naturally lost pace with new developments. In fact, it has lost pace to such an extent that most new, genetically based cancer tests are likely to have been regulated as general IVDs, including companion diagnostics.
Most IVDs are categorised as general IVDs. Consequently, the majority of IVDs on the market have been self-certified by the manufacturer. This means that to date, IVDs have required limited notified body involvement, and responsibility has been placed on the manufacturer to ensure compliance to essential requirements and performance characteristics for around 80% of IVDs.
With the new IVD Device Regulation in Europe, IVD products remain distinct from the now consolidated regulation for medical devices and active implantable medical devices. It makes sense for IVDs to continue to be regulated separately, as there are many differences between the two groups, including the indirect application and risk.
The IVD Device Regulation has several changes and requirements in common with the new medical device regulation, such as the requirement for a person responsible for regulatory compliance, increased focus on unannounced audits and unique device identifiers (UDIs). However, for IVDs, unlike medical devices, there have not been high-profile post-market events, such as the metal-on-metal implant issues or the PIP (Poly Implant Prosthèse) scandal. Given the relatively safe profile of IVDs, a lot of additional regulatory oversight will come with the new IVD Device Regulation.
The regulation introduces four classes, Class D being the highest risk and Class A the lowest
The new regulation brings into place a risk-based classification system, moving away from positive inclusion. The regulation introduces four classes, Class D being the highest risk and Class A the lowest, thereby providing greater regulatory agility. Only Class A devices that are not for self-testing, sterile or for near patient testing, escape direct notified body product review, only around 20% of IVDs. A significant contrast for both the regulators and industry.
What is an IVD?
An IVD can be anything from a specimen receptacle, to a urine test, to a molecular diagnostic screening instrument. The key differentiator is that IVDs never interact directly with the human body, as their diagnostic purpose is based on specimens derived from the human body, for example a blood glucose meter. A test that analyses body fluids directly, for example a continuous glucose meter, would be regulated as a medical device instead.
What is conformity assessment?
Conformity assessment is the process by which products are assessed against the requirements of the directive in order for the products to be CE marked and placed on the market. For lower risk devices conformity assessment is often performed by the manufacturer, whereas for higher risk devices an independent and authorised party, the notified body, may be involved in the assessment process.
What are companion diagnostics?
A device that is essential for the safe and effective use of corresponding medicinal products. They can be used to identify patients that are likely to benefit, or patients who are at risk of adverse reactions or to monitor responses to treatment.
What are self testing IVDs?
Devices for testing carried out by lay persons.
What is ‘near patient testing’?
The use of devices for testing carried out outside of controlled laboratory conditions, generally by a health professional near to the patient.
Brace for impact
Moving to a classification system for IVDs allows for the regulatory framework to remain more agile as technology develops. For newly classified B to D IVDs, the classification changes are significant for the industry, as there may be further administrative burdens on many small- and medium-sized companies in this sector. The change will require involvement of notified bodies during the conformity assessment before a product can be placed on the market, and for many IVD manufacturers this will be a new experience.
For companion diagnostics, the changes under the new regulation are even more significant as many of these IVDs are currently self-certified. The new regulation introduces a definition and special provisions for companion diagnostics, to be regulated as Class C. In addition, for companion diagnostics, the proposed regulatory changes include European Medical Agency (EMA) involvement. This unique requirement has caused industry concern since the EMA are likely to be already involved in with the regulation of the companion drug and the review process is currently unclear.
Clinical evidence will be required throughout the product lifecycle of IVDs, including scientific validity, analytical performance and clinical validity. This means that the amount of performance evaluation and the number of clinical studies are likely to increase, adding further cost to development. Manufacturers will also face a stronger post-market element with continual assessment of new scientific evidence to determine any impact on clinical validity. In-house developed tests (e.g. those developed and performed by hospital laboratories) will be exempt from the regulation for all bar some specific provisions for Class D devices. This exemption is if they are used in facilities running under the same quality management system, typically to ISO 15189.
Currently this exemption extends to in-house companion diagnostics, potentially raising further concern by industry due to the difference in costs of development and regulatory scrutiny. The new IVD Regulation certainly brings about significant change for both the industry and the regulators. However, it is likely that for several manufacturers similar processes have been undertaken to place the product in the US or Canadian markets. There is only a little time, with the new IVD Regulation expected to have a 5-year implementation period. During this time, it will be important for the industry and regulators to remain proactive and responsive, implementing the necessary changes.
All change please, all change.
98/79/EC, European Parliament and of the Council, 1998.
93/42/EC, European Parliament and of the Council, 1993.
EDMA analysis of proposed Regulation on in vitro diagnostic medical devices, EDMA, 2013.
Position of the Council at first reading with a view to the adoption of a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU, European Council, 2017.
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